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EMBO Rep ; 19(6)2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29674348

RESUMO

Th17 cells contribute to the development of autoimmune diseases by secreting interleukin-17 (IL-17), which activates its receptor (IL-17R) that is expressed on epithelial cells, macrophages, microglia, and resident neuroectodermal cells. However, the mechanisms through which IL-17R-mediated signaling contributes to the development of autoimmune disease have not been completely elucidated. Here, we demonstrate that Raf-1 kinase inhibitor protein (RKIP) deficiency in mice ameliorates the symptoms of experimental autoimmune encephalomyelitis (EAE). Adoptive T-cell-transfer experiments demonstrate that RKIP plays a predominant role in Th17-mediated, but not in Th1-mediated immune responses. RKIP deficiency has no effect on Th17-cell differentiation ex vivo, nor does it affect Th17-cell differentiation in EAE mice. However, RKIP significantly promotes IL-17R-induced proinflammatory cytokine and chemokine production. Mechanistically, RKIP directly interacts with IL-17RA and Act1 to promote the formation of an IL-17R-Act1 complex, resulting in enhanced MAPK- and P65-mediated NF-κB activation and downstream cytokine production. Together, these findings indicate that RKIP functions as an essential modulator of the IL-17R-Act1 axis in IL-17R signaling, which promotes IL-17-induced inflammation and autoimmune neuroinflammation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Proteína de Ligação a Fosfatidiletanolamina/fisiologia , Receptores de Interleucina-17/metabolismo , Células Th17/imunologia , Animais , Encefalomielite Autoimune Experimental/genética , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Ligação a Fosfatidiletanolamina/genética , Transdução de Sinais
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